CN109776416A - A kind of bulleyaconitine A C crystal form and the preparation method and application thereof - Google Patents
A kind of bulleyaconitine A C crystal form and the preparation method and application thereof Download PDFInfo
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- CN109776416A CN109776416A CN201910197723.8A CN201910197723A CN109776416A CN 109776416 A CN109776416 A CN 109776416A CN 201910197723 A CN201910197723 A CN 201910197723A CN 109776416 A CN109776416 A CN 109776416A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The present invention relates to field of medicinal chemistry, and the invention discloses bulleyaconitine A C crystal form and the preparation methods of bulleyaconitine A C crystal form.Crystal form of the present invention is as shown in Figure 1 using the X-ray powder diffraction spectrogram that Cu-K alpha ray measurement obtains.Bulleyaconitine A C crystal form is obtained using DMF as solvent using gas-solid osmosis, and preparation process is simple, and the crystal form purity obtained is high, through XRD, DSC, TGA,1The characterization of HNMR, is determined as C crystal form.Gained bulleyaconitine A crystal is solvate crystal form, through stability test, the results showed that the crystal is to light, wet, good thermal stability.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of bulleyaconitine A C crystal form and the preparation method and application thereof.
Background technique
Bulleyaconitine A chemical name is (1 α, 6 α, 14 α, 16 β) tetrahydro -8,13,14- triol -20- ethyl -1,6,16- tri-
Methoxyl group -4- methoxyl methyl -8- acetoxyl group -14- (4 '-are to methoxybenzene methyl esters)-aconitane.It is from Ranunculaceae Aconitum
Plant --- a kind of diterpene di esters that extracting and developing goes out in the long beak rhizome of Chinese monkshood (Aconitum georgei Comber) root tuber is raw
Alkaloids are named as crassicauline (Crassicauline A), be renamed as later bulleyaconitine A (Bulleyaconitine A,
T2), belong to the known native compound in plant species, structural formula is as follows:
At present bulleyaconitine A preparation be clinically widely used in treatment rheumatoid arthritis (RA), osteoarthritis, myofibrositis,
Chronic ache caused by neck and shoulder ache, pain in waist and lower extremities, cancer pain and a variety of causes.
Polymorph in pharmaceuticals is the common phenomenon in drug research and development, is an important factor for influencing drug quality.Crystal form is different
Same drug appearance, solubility, fusing point, dissolution rate and in terms of have difference, in some instances it may even be possible to have significant
Difference, thus, it will affect stability, bioavilability and curative effect of drug etc..And the crystal form of drug also will affect drug
The quality of pharmaceutical formulation, the absorption behavior in human body, and finally influence therapeutic effect and secondary work that said preparation generates in human body
Benefit ratio.As the research of bulleyaconitine A is goed deep into, carry out the research such as bulleyaconitine A crystal form, physicochemical property for bulleyaconitine A
Drug effect, quality, the evaluative meaning of drug safety are great.Application No. is 201710423005.9 Chinese patents to disclose radix aconiti agrestis
The A prime organic solvent of C1-C4 dissolves, and obtained bulleyaconitine A solution is added dropwise in water, stirring while adding, finishes, filters,
Amorphous bulleyaconitine A is made in filtration cakes torrefaction.The also not relevant report about crystalline state bulleyaconitine A at present.
Summary of the invention
In view of this, it is an object of the present invention to provide novel crystal forms of bulleyaconitine A and preparation method thereof.
It is an object of the invention to by crystallographic method, study, find and provide the crystalline of bulleyaconitine A
Formula C crystal form.
The present invention studies and characterizes the knot of bulleyaconitine A using x-ray powder diffraction (XRPD) generally acknowledged in the world
Crystalline form.Determination condition and method: Cu/K-alpha1 (target), 45KV-40mA (operating voltage and electric current), 2 θ=3-40 (scanning
Range), every step sweep time (s) is 17.8-46.7, and scanning step (2 θ) is 0.0167-0.0263,
Essentially pure C crystal form provided by the invention, X-ray powder diffraction figure is as shown in Figure 1, its x-ray powder
Diffraction pattern has bright at 2 θ values is 5.8 ± 0.2,6.3 ± 0.2,10.8 ± 0.2,11.8 ± 0.2,13.8 ± 0.2,17.5 ± 0.2
Aobvious characteristic absorption peak.
The present invention uses thermogravimetry also to study and characterize bulleyaconitine A C crystal form.Testing conditions are as follows: opened from room temperature
Begin, heating gradient: is warming up to 400 DEG C with the speed of 10 DEG C/min, protective gas is nitrogen.
Essentially pure bulleyaconitine A C crystal form provided by the invention, thermal gravimetric analysis curve is as shown in Fig. 2, it has
Following characteristic: sample TGA weightlessness 15.93%, when being heated to 60 DEG C, weightlessness is 8.58%；When being heated to 120 DEG C, weightlessness is
7.35%.
The present invention uses differentia scanning calorimetry also to study and characterize bulleyaconitine A C crystal form.Detection method be from
25 DEG C of beginnings, heating gradient: are warming up to 280 DEG C with the speed of 10 DEG C/min, protective gas is nitrogen.
Essentially pure bulleyaconitine A C crystal form provided by the invention, differential scanning calorimetric analysis curve such as Fig. 2 institute
Show, has the property that on its differential scanning calorimetric analysis curve respectively at 67.1 DEG C, 81.6 DEG C, 123.7 DEG C, 173.8 DEG C
There is endothermic signal.
It is worth noting that, for the X-ray powder diffraction figure of crystal form described above, in a machine and another machine
Between device and between a sample and another sample, the characteristic peak of X-ray powder diffraction figure may be slightly changed,
Numerical value may differ by about 1 unit, perhaps differs about 0.8 unit and perhaps differs about 0.5 unit or difference
About 0.3 unit, or difference about 0.1 unit, therefore given numerical value cannot be considered as it is absolute.The same above institute
State numerical value given by the differential scanning calorimetric analysis curve graph of crystal form can not be considered as it is absolute.
Crystal form can also use technically well known other analytical technologies characterization.Such as nuclear magnetic resonance spectroscopy (1HNMR)。
Essentially pure bulleyaconitine A C crystal form provided by the invention, hydrogen nuclear magnetic resonance spectrogram are as shown in Figure 3.
The present invention also provides the preparation methods of the bulleyaconitine A C crystal form of purity is high.
The preparation method of the bulleyaconitine A C crystal form provided by the invention is to be obtained using DMF as solvent using gas-solid osmosis
?.Concrete operations are that bulleyaconitine A is placed in bottle, separately take slightly larger bottle and DMF is added thereto, bottle opening is placed in
It in slightly larger bottle, is stood at room temperature after sealing, collects solid to obtain the final product.
Bottle opening is placed in slightly larger bottle in the preparation method of bulleyaconitine A C crystal form of the present invention, room temperature after sealing
Lower time of repose is no less than 2 days.
Bulleyaconitine A C crystal form preparation method of the present invention obtains crystal form content and is greater than 99%, with high purity, X-ray powder
Difraction spectrum feature and DSC characteristic spectrum are consistent, and property is stablized, to light, wet, good thermal stability.
The present invention also provides the bulleyaconitine A C crystal forms to close in preparation prevention and/or treatment rheumatoid arthritis RA, bone
Save the application in inflammation, myofibrositis, neck and shoulder ache, pain in waist and lower extremities or cancer pain drug.
As shown from the above technical solution, the invention discloses the preparation sides of bulleyaconitine A C crystal form and bulleyaconitine A C crystal form
Method.Crystal form of the present invention is as shown in Figure 1 using the X-ray powder diffraction spectrogram that Cu-K alpha ray measurement obtains.Bulleyaconitine A C
Crystal form is obtained using DMF as solvent using gas-solid osmosis, and preparation process is simple, and the crystal form purity obtained is high, through XRD,
DSC、TGA、1The characterization of HNMR, is determined as C crystal form.Gained bulleyaconitine A crystal is solvate crystal form, through stability test,
The result shows that the crystal is to light, wet, good thermal stability.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
The XRPD of Fig. 1 crystal form C schemes；
The TGA/DSC of Fig. 2 crystal form C schemes；
Fig. 3 crystal form C's1HNMR map.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
For a further understanding of the present invention, the present invention will be described in detail combined with specific embodiments below.Following implementations
In example, unless otherwise indicated, the test method is usually according to normal condition or the condition of manufacturer's suggestion is implemented.It is used
Reagent is analyzed pure.
Crystal form characterization test parameter:
XRPD figure acquires on PANalytacal Empyrean and X ' Pert3X ray powder diffraction analysis instrument, scanning ginseng
Number is as shown in table 1.
1 XRPD test parameter of table
Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)
TGA and DSC figure is respectively in TA Q5000TGA/TA Discovery TGA5500 thermogravimetric analyzer and TA
It is acquired on Q2000DSC/TA Discovery DSC2500 differential scanning calorimeter, table 2 lists test parameter.
2 TGA and DSC test parameter of table
| Parameter | TGA | DSC |
| Method | Linear temperature increase | Linear temperature increase |
| Sample disc | Aluminium dish is opened wide | Aluminium dish, gland |
| Temperature range | Room temperature-setting outlet temperature | 25 DEG C-setting outlet temperature |
| Sweep speed (DEG C/min) | 10 | 10 |
| Protective gas | Nitrogen | Nitrogen |
Liquid nuclear-magnetism
Liquid nuclear magnetic spectrogram acquires in Bruker 400M Nuclear Magnetic Resonance, and DMSO-d6 is as solvent.
The preparation and authentication of embodiment 1, bulleyaconitine A C crystal form
It is obtained using gas-solid osmosis, specific preparation step are as follows: weigh 14.7 milligrams of bulleyaconitine As and be placed in 3 milliliters of bottles
In, it separately takes 20 milliliters of bottles and 2 milliliters of DMF is added thereto, 3 milliliters of bottle openings are placed in 20 milliliters of bottles, after sealing
Stand at room temperature, after about 6 days, collect solid and carry out XRPD, TGA/DSC and1HNMR test.
XRPD the result shows that, the angle of diffraction (2 angle θ) be 5.8 ± 0.2,6.3 ± 0.2,10.8 ± 0.2,11.8 ± 0.2,
There is apparent characteristic absorption peak at 13.8 ± 0.2,17.5 ± 0.2.TGA/DSC the result shows that, it is weightless when sample is heated to 60 DEG C
It is 8.5%；Occur multiple endothermic signals on DSC curve.1HNMR the result shows that, 1.68 moles of DMF are detected in sample
(16.02wt%).
It is accredited as crystal form C, solvate.
Map is shown in the X-ray powder diffraction figure of Fig. 1 bulleyaconitine A C crystal form, the TGA/ of Fig. 2 bulleyaconitine A C crystal form respectively
Dsc analysis figure, Fig. 3 bulleyaconitine A C crystal form1HNMR figure.
The preparation of embodiment 2, bulleyaconitine A C crystal form
It is obtained using gas-solid osmosis, specific preparation step are as follows: weigh 14.7 milligrams of bulleyaconitine As and be placed in 3 milliliters of bottles
In, it separately takes 20 milliliters of bottles and 2 milliliters of DMF is added thereto, 3 milliliters of bottle openings are placed in 20 milliliters of bottles, after sealing
It stands at room temperature, after 2 days, collects solid and carry out XRPD test, it is as a result consistent with Fig. 1.
The preparation of embodiment 3, bulleyaconitine A C crystal form
It is obtained using gas-solid osmosis, specific preparation step are as follows: weigh 14.7 milligrams of bulleyaconitine As and be placed in 3 milliliters of bottles
In, it separately takes 20 milliliters of bottles and 2 milliliters of DMF is added thereto, 3 milliliters of bottle openings are placed in 20 milliliters of bottles, after sealing
It stands at room temperature, after 20 days, collects solid and carry out XRPD test, it is as a result consistent with Fig. 1.
The stability test of embodiment 4, bulleyaconitine A C crystal form
In order to assess the solid-state stability of crystal form, appropriate amount of sample is weighed respectively in 25 DEG C/60%RH and 40 DEG C/75%RH item
Part lower open mouth is placed 1 week and 1 month, and sealing is placed 24 hours under the conditions of 80 DEG C.To after placement sample carry out XRPD and
HPLC characterization, to detect crystal form variation and chemical purity.
HPLC the results are shown in Table 3, the results showed that the chemical purity of sample does not almost change in selected test condition；
XRPD is not the result shows that the crystal form of sample changes in selected test condition.
The stability data of 3 crystal form C of table summarizes
Conclusion, crystal form C have good physics and chemical stability.
Claims (8)
1. bulleyaconitine A C crystal form, which is characterized in that its X-ray powder diffraction figure is 5.8 ± 0.2,6.3 ± 0.2 in 2 θ values,
There is apparent characteristic absorption peak at 10.8 ± 0.2,11.8 ± 0.2,13.8 ± 0.2,17.5 ± 0.2.
2. crystal form according to claim 1, which is characterized in that when being heated to 60 DEG C, weightlessness is its thermal gravimetric analysis curve
8.58%；When being heated to 120 DEG C, weightlessness is 7.35%.
3. crystal form according to claim 1, which is characterized in that its differential scanning calorimetric analysis curve respectively 67.1 DEG C,
81.6 DEG C, 123.7 DEG C, 173.8 DEG C there is endothermic signal.
4. crystal form according to claim 1, which is characterized in that its hydrogen nuclear magnetic resonance spectrogram is as shown in Figure 3.
5. the preparation method of bulleyaconitine A C crystal form described in claim 1, which is characterized in that using DMF as solvent, using gas-solid
Osmosis obtains.
6. preparation method according to claim 5, which is characterized in that the gas-solid osmosis is specially to set bulleyaconitine A
In bottle, separately takes slightly larger bottle and DMF is added thereto, bottle opening is placed in slightly larger bottle, it is quiet at room temperature after sealing
It sets, collects solid.
7. preparation method according to claim 6, which is characterized in that the bottle opening is placed in slightly larger bottle after sealing
Time of repose is no less than 2 days at room temperature.
8. bulleyaconitine A C crystal form described in claim 1 is in preparation prevention and/or treatment rheumatoid arthritis RA, osteoarthritis, flesh
Application in fibrositis, neck and shoulder ache, pain in waist and lower extremities or cancer pain drug.
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| CN201910197723.8A CN109776416B (en) | 2019-03-15 | 2019-03-15 | Bulleyaconitine A C crystal form and preparation method and application thereof |
| PCT/CN2020/076154 WO2020186960A1 (en) | 2019-03-15 | 2020-02-21 | Bulleyaconitine a crystalline form c, preparation method therefor and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186960A1 (en) * | 2019-03-15 | 2020-09-24 | 云南昊邦制药有限公司 | Bulleyaconitine a crystalline form c, preparation method therefor and application thereof |
| CN111875541A (en) * | 2020-07-03 | 2020-11-03 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polymorphism, preparation method and application thereof |
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|---|---|---|---|---|
| CN101555227A (en) * | 2009-05-19 | 2009-10-14 | 昆明制药集团股份有限公司 | Preparation method of high purity bulleyaconitine A |
| CN101830849A (en) * | 2010-05-10 | 2010-09-15 | 张红彬 | Method for preparing simplified high-purity bulleyaconitine A |
| CN102924376A (en) * | 2012-11-28 | 2013-02-13 | 云南省农业科学院药用植物研究所 | Method for preparing high-purity bulleyaconitine A |
| CN104326981A (en) * | 2014-10-16 | 2015-02-04 | 云南大围山生物制药有限公司 | Bulleyaconitine A efficient extraction and separation method |
| CN106008344A (en) * | 2016-06-03 | 2016-10-12 | 云南中医学院 | Bulleyaconitine A preparation method |
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| CN109776416B (en) * | 2019-03-15 | 2021-01-12 | 云南昊邦制药有限公司 | Bulleyaconitine A C crystal form and preparation method and application thereof |
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| CN101555227A (en) * | 2009-05-19 | 2009-10-14 | 昆明制药集团股份有限公司 | Preparation method of high purity bulleyaconitine A |
| CN101830849A (en) * | 2010-05-10 | 2010-09-15 | 张红彬 | Method for preparing simplified high-purity bulleyaconitine A |
| CN102924376A (en) * | 2012-11-28 | 2013-02-13 | 云南省农业科学院药用植物研究所 | Method for preparing high-purity bulleyaconitine A |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186960A1 (en) * | 2019-03-15 | 2020-09-24 | 云南昊邦制药有限公司 | Bulleyaconitine a crystalline form c, preparation method therefor and application thereof |
| CN111875541A (en) * | 2020-07-03 | 2020-11-03 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polymorphism, preparation method and application thereof |
| CN115650917A (en) * | 2020-07-03 | 2023-01-31 | 上海品姗医药咨询有限公司 | Bulleyaconitine A polycrystalline type and preparation method and application thereof |
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